ABSTRACT
Pteridine reductase 1 (PTR1) is a unique enzyme required for survival of Leishmania species, a causative organism forthe disease leishmaniasis. We herein report the design, docking, and Absorption, Distribution, Metabolism, Excretion,Toxicity (ADMET) prediction studies of 2-substituted-5-[(6-substituted-1H-benzimidazol-2yl)methyl]azole derivatives(B1–B14) as PTR1 inhibitors. Molecular docking studies showed good binding interaction of the compounds withthe active site of pteridine reductase from Leishmania Major, with compounds B5 and B12 showing docking scoresof −61.5232 and −62.5897, respectively, which were comparable with the original ligand, dihydrobiopterin. Largesubstituents on the azole ring, as well as substitutions on sixth position of the benzimidazole ring, were found to befavorable for interaction with PTR1 active site. Physicochemical properties, bioactivity prediction, and toxicity profilesof the compounds were studied using the Molinspiration and admetSAR web servers. All compounds followed Lipinski’srule of five and can be considered as good oral candidates. Bioactivity prediction indicated that the compounds wereenzyme inhibitor, thus the rationale for designing PTR1 inhibitors was met. Most of the compounds were predicted tohave good ADMET properties in terms of Gastrointestinal (GI) absorption, absence of P-glycoprotein interaction, andLD50 values in rats. The designed molecules can be further explored for their antileishmanial activity